Crohn's disease (CD) and Ulcerative Colitis (UC) are the two major types of Inflammatory Bowel Disease (IBD)—a generic classification for a group of nonspecific, idiopathic inflammatory disorders of the gastrointestinal (GI) tract which also includes Indeterminate Colitis (IC). Indeterminate Colitis refers to the up to 15% of IBD cases where distinguishing between CD and UC is impossible. (Kasper, 2008) Both CD and UC tend to be chronic in nature and run a course characterized by exacerbations and remissions.
CD may occur in any part of the GI tract, but most commonly affects the distal ileum and colon. It is characterized by transmural inflammation of the gastrointestinal wall, interspersed with “skip” areas of normal tissue, leading to the characteristic endoscopic and radiographic appearance of the disease. In about half the cases, biopsy specimens reveal the pathognomonic histology of noncaseating granulomas (Friedman, 2001).
Although CD usually presents as acute or chronic bowel inflammation, the inflammatory process evolves toward one or two patterns of disease: a fibrostenotic-obstructing pattern or a penetrating-fistulous pattern, each with different treatments and prognoses (Friedman, 2001).
Even though the most common initial presentation of Crohn's disease is purely inflammatory, without fistulizng or perforating complications, more than 70% of CD patients progress to a more complicated disease course within 10 years of diagnosis. More than one-third of these patients develop a distinct fibrostenosing phenotype that manifests by progressive narrowing of the bowel lumen with the potential of intestinal obstruction. It is currently unknown which CD patients will develop a fibrostenotic disease phenotype and in what time frame these changes may occur (Rieder, 2011). Fibrostenotic Crohn's disease does not respond to medical therapy and requires endoscopic or surgical treatment (Foehlich, 2007).
The characteristic inflammatory presentation of Crohn's disease is of abdominal pain, diarrhea, fever and weight loss which may be complicated by intestinal fistulization, obstruction, or both. Fistula formation may occur to the adjacent bowel, the skin, the urinary bladder, or other locations. Obstruction, if present, is initially intermittent due to bowel wall edema and spasm; further progression may lead to chronic scarring and stricture formation. Perianal disease is common and may manifest as anal fissure, perianal fistula, or abscess (Friedman, 2001; Wu, 2007).
Extra-intestinal manifestations may also occur and include joint inflammation (e.g., peripheral arthritis, ankylosing spondylitis), skin lesions (e.g., erythema nodosum, pyoderma gangrenosum), ocular involvement (e.g., iritis, uveitis) and liver disorders (e.g., hepatic steatosis, primary sclerosing cholanitis) (Friedman, 2001; Wu, 2007).
The incidence of CD varies within different geographic areas. Northern countries such as the US, UK, Norway and Sweden have the highest rates. The incidence of CD in the US is approximately 7 per 100,000. Countries in southern Europe, South Africa and Australia have lower incidence rates of 0.9 to 3.1 per 100,000. The disease is rare in Asia and South America (Friedman, 2001).
The peak age of onset of Crohn's disease occurs between the ages of 15 and 30 years, with a second peak of occurrence between the ages of 60-80 years (Friedman, 2001).
The fundamental cause of CD is unknown. There are four basic factors affecting the pathophysiology of CD: genetics, immune dysregulation, epithelial barrier dysfunction and the constitution of microbial flora. Evidence suggests that genetic predisposition leads to an unregulated intestinal immune response to an environmental, dietary or infectious agent (Friedman, 2001; Wen, 2004). A number of studies suggest that CD is a T-helper 1 (Th-1) mediated disease and that the excessive Th1-cell activity leading to the production of a wide range of proinflammatory cytokines [including interleukin (IL)-1, IL-2 and tumor necrosis factor (TNF)-α] and an imbalance between proinflammatory and anti-inflammatory reactivity, is a critical component of CD (Hendrickson, 2002). However, no inciting antigen has been identified.
In the absence of a key diagnostic test, the diagnosis of Crohn's disease is based on endoscopic, radiographic and pathological findings documenting focal, asymmetric transmural or granulomatous features. Laboratory abnormalities include non-specific markers of inflammation such as elevated sedimentation rate and C-reactive protein (CRP). In more severe cases, finding may include hypoalbuminemia, anemia, and leukkocytosis (Friedman, 2001; Wu, 2007).
There is no definitive treatment or cure for CD. The major therapeutic goals are the reduction of signs and symptoms, induction and maintenance of remission and most importantly, the prevention of disease progression and complications.
Sulfasalazine and other 5-aminosalicylic acid agents, antibiotics such as metronidazole and ciprofloxacin, corticosteroids, immunosupressors such as azathioprine and 6-mercaptopurine and biologic agents such as anti-TNFα agents and anti-integrins that prevent leukocyte infiltration have shown to be useful in the induction of remission and/or in its maintenance (Targan, 1977; Hanauer, 2002; Colombel, 2007; Ghosh, 2003; Sandborn, 2005; Schreiber, 2005; Schreiber, 2007; Kozuch, 2008). Many of these medicinal products, however, are only moderately efficacious and are associated with challenging side effects (Hommes, 2003; Thomas, 2004; Colombel, 2004; Van Assche, 2005; Vermeire, 2003; Sweetman, 2006). In addition, the newer biologic agents have a relatively inconvenient parenteral route of administration.
Loss of response to anti-TNFαs at 12 months of therapy occurs in 23-46% of patients when judged by dose intensification, or 5-13% when gauged by drug discontinuation rates. The management of loss of response should allow for a period of watchful waiting as quite often the patients' symptoms may resolve without alteration of therapy. If they do not, then identifying the correct mechanism responsible for clinical deterioration is prudent. Once symptoms are ascertained to arise from inflammatory IBD activity, drug level and antidrug antibody measurement can then help distinguish between non-adherence to therapy, immunogenicity and non-immune clearance of anti-TNFα, or an un-chequered inflammation despite adequate anti-TNFα levels. The latter finding may be best addressed by a switch to another class of immunomodulators, whereas a low drug level should probably be managed by dose intensification or a switch to another anti-TNFα (S. Ben-Horin; Alimentary Pharmacology & Therapeutics. 2011; 33(9):987-995.).
There is, therefore, a definite need for alternative therapies with better risk-benefit profiles and a more convenient route of administration than the currently available options.
Disclosed is a method of treating Crohn's disease using laquinimod. Laquinimod is a novel synthetic compound with high oral bioavailability, which has been suggested as an oral formulation for Relapsing Remitting Multiple Sclerosis (MS).
Laquinimod and its sodium salt form are described, for example, in U.S. Pat. No. 6,077,851.